Review Article
Current status and future challenges of brain imaging with 18F-DOPA PET for movement disorders
Abstract Ferdinando Franco Calabria1 MD, 2 Objective: Parkinson's disease (PD) is a neurodegenerative disorder (ND) due to progressive loss of Eros Calabria MD, dopaminergic neurons in the basal ganglia. The correct di erential diagnosis of this disease with Vincenzo Gangemi3 MD, 4 parkinsonian syndromes (PS) or with essential tremor (ET) is a diagnostic dilemma, considering that only Giuseppe Lucio Cascini MD PD is responsive to treatment with levodopa. Traditional imaging fails to diagnose PD because morphological alterations in the brain are usually detectable only at advanced stages. Single photon emission tomography (SPET) with cocaine analogues has recently been used in the early detection of PD. The uoro-18-deoxyphenyl-alanine (18F-DOPA) is a positron emission tomography (PET) tracer with 1. Neuroimaging PET/MRI Research selective in vivo a nity to the basal ganglia, due to the speci c metabolism of substantia nigra. We Unit, Institute of Molecular Bioimaging assessed the e ective use of 18F-DOPA PET in brain imaging in order to describe the function of and Physiology, National Research presynaptic disorders of PD, PS, ET and other movement disorders compared to SPET imaging and also Council, Catanzaro, IBFM CNR, Italy discussed novel radiopharmaceuticals. The role of magnetic resonance imaging (MRI) was also discussed. 2. Department of Diagnostic Conclusion: The 18F-DOPA PET imaging is still the best diagnostic tool for the diagnosis of PD and other and Molecular Imaging, movement disorders. Fluorine-18-FDG PET can play a role in the di erential diagnosis between PD and Interventional Radiology and other PS. The hybrid 18F-DOPA PET/MRI seems to be able to play an important additional role in early Radiotherapy, PTV Foundation, diagnosis of the above syndromes. University of Rome "Tor Vergata", Rome, Italy 3. Department of Experimental Hell J Nucl Med 2016; 19(1): 33-41 Epub ahead of print: 1 March 2016 Published online: 1 April 2016 and Clinical Medicine, Nuclear Medicine Unit,Magna Graecia University,Catanzaro, Italy 4. Department of Diagnostic Imaging, Nuclear Medicine Unit, Introduction Magna Graecia University, Catanzaro, Italy
arkinson's disease (PD) is a neurodegenerative disorder (ND) due to the Keywords: 18F-DOPA, PET/CT progressive loss of dopaminergic neurons in the basal ganglia. Neurons in the putamen usually present the most severe impairment compared to those in - inetics in Parkinson's disease P caudate nucleus. Several ND such as progressive supranuclear palsy (PSP), multiple - Molecular Imaging - PET/MRI system atrophy (MSA) and corticobasal degeneration (CBD) are characterized by a - Movement Disorders complex of symptoms often mimicking PD. Essential tremor (ET) clinically may also - Parkinsonian Syndromes mimic PD, because both have a predominant postural/action tremor. Di erential diagnosis between PD, PS and ET can be di cult. In many cases, a middle term clinical follow-up is necessary. Almost 25% of patients with initial diagnosis of PD are postmortem diagnosed having ET [1-3]. Corresponding author: In early stages and in monitoring changes of disease activity in PD and other ND, Ferdinando Franco Calabria MD, magnetic resonance imaging (MRI) and computed tomography (CT), are usually not Institute of Molecular Bioimaging diagnostic. and Physiology, National Research Parkinson's disease (PD) is associated with loss of vesicular monoamine transporter Council, IBFM CNR, Viale Europa 88100, Germaneto, type 2 (VMAT2) and dopamine transporters (DAT) binding. This loss appears 13-17 years Catanzaro, Italy, Tel: +39 328 prior to the onset of the disease, as demonstrated by single photon emission 3337036 tomography (SPET) with tracers imaging presynaptic receptors [4-7] . [email protected] Single photon emission tomography with cocaine analogue receptors is used to study the integrity of dopaminergic neurons in PD. [8-9]. Other studies with uorine-18- dihydroxy-phenylalanine (18F-DOPA) gave promising results in diagnosing early stages of PD and its deferential diagnosis with ET. The unique sites of physiological uptake of 18F- Rece ved: DOPA in the brain are the basal ganglia, caudatum and putamen, due to the speci c 20 December 2015 metabolism of the substantia nigra [10] . Positron emission tomography (PET) with 18F- Accepted rev sed: DOPA is also useful in the management of patients with other movement disorders. 27 February 2016 We also reviewed in the literature 18F-DOPA PET imaging using cocaine analogues or other
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radiopharmaceuticals, with SPET or PET and also PET/MRI in drugs shall not interfere with the uptake of the tracer . Such diagnosing PD and other ND. a drug is levodopa, which follows the same molecular path- We used the 1990-2015 Medline data bases through the way in crossing BBB and can thus increase the distribution following keywords: ''18F-DOPA AND PET OR PET/CT volume of 18F-DOPA in the brain [16] . Other such drugs are AND Parkinson's disease AND/OR essential tremor halo-peridol, reserpine [17] and entacapone [18] . Drugs AND/OR movement disorders AND/OR progressive that in uence the function of LAT and can interfere with 18F- supranuclear palsy AND/OR multiple system atrophy DOPA as above are melphalan, thyroxine and baclofen [19] . AND/OR cortico-basal ganglia degeneration . Furthermore, On a theoretical basis, it is necessary, 24 hours before the other research data were obtained using the following test to abstain from taking proteins. It has been keywords: 18F-DOPA AND PET OR PET/CT AND 18F-FDG documented that some aromatic amino acids compete with 18 AND/OR 18F- uoroethyltyrosine AND/OR Datscan F-DOPA at the level of LAT transporters [20] . AND/OR SPET AND/OR MRI AND/OR PET/MRI . From 1986 till mid 2015, our Medline research generated 86 papers out of which we analyzed 40 papers. The inclusion criteria were: a) The English language, b) Human studies, c) Original articles, d) Reviews, clinical trials or case reports. Twelve of these selected articles compared SPET with cocaine analogues or PET with 18F-DOPA or with other radiopharmaceuticals. The references of eight of the enrolled articles were also read for additional information concerning the synthesis of 18F-DOPA. Other eleven references gave information about the physiological distribution of the tracers in the brain and the whole human body. Finally, seven references gave additional information about the future perspectives of MRI and PET/MRI for PD and ND.
Synthesis, biokinetics, physiological distribution and variants of 18F-DOPA Figure 1. A diagram of premedication with carbidopa reducing the catechol-O- methyltransferase peripheral activity and enhancing availability of 18F-DOPA in the brain and its conversion to 18F-DOPA. Fluorine-18-DOPA can be synthesized by an electrophilic or nucleo-philic process. The electrophilic process uses the 18 destannylation of F-DOPA precursor and has become the No adverse reactions have been reported, except a short, best technique in synthesizing 18F-DOPA, with uorination 18 transient mild pain and/or irritation at the site of the of L-3-(3-hydroxy-4-pivaloyloxyphenyl)-alanine and F-ace- intravenous (i.v.) administration of the radiopharmaceutical. tyl hypo uorite in acetic acid, followed by HCl hydrolysis Therefore, it appears necessary to slowly administer the and high-performance liquid chromatography. This has tracer through a venous catheter [21] . been shown to be the best routine method for the synthesis 18 18 Regarding the imaging acquisition protocol of F-DOPA of F-DOPA, allowing a radiochemical purity of 97% [11]. PET for semi quantitative or visual analysis, many authors Being the precursor of L-DOPA, the 18F-DOPA follows in suggest after tracer administration, to perform a dynamic central nervous system and in whole human body the same scan at 90 min, which is considered the time of the highest metabolic pathway as L-DOPA. In fact, both penetrate the uptake of the tracer in the basal ganglia [22]. Other cells carried by the L-type amino acid transporter 1 and 2 acquisition protocols linked to brain tumor processes (LAT1 and LAT2). These transporters are enrolled in the 18 suggest to perform the examination 20 minutes after the permeability of the blood brain barrier (BBB) of F-DOPA . Subsequently, 18F-DOPA is converted to 6-[18F] uorodo- administration of the tracer [23]. Considering the above, pamine-18F-FDOPA) by the amino acid decarboxylase Dhawan et al. (1996) [24] suggested to exclusively use only one single point late acquisition protocol. (AAAD) [11,12]. The tracer can be also metabolized in several 18 perip-heral tissues by catechol-o-methyl transferase (COMT) Whole body normal distribution of F-DOPA mainly refers befo-re crossing BBB, thus reducing brain uptake. The to liver, pancreas, adrenal glands, gallbladder, kidneys and premedi-cation of patients before tracer administration with urine bladder. The basal ganglia are normally visualized, carbi-dopa per os can reduce the COMT peripheral activity, while amygdala and thalamus show a minimal or negligible conse-quently enhancing availability of the 18F-DOPA in the uptake of the tracer [25]. Concerning the excretion of the brain and its conversion to 18F-FDA [13] (Figure 1). tracer, 50% of the administered radiopharmaceutical is Most centers ask patients to fast for 4-6 hours and abstain excreted during the rst hour in the urine while the rest is from drugs for 24 hours before tracer administration, so that excreted during the next 12 hours [17,26].
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Parkinson's Disease Various authors in PD have demonstrated that on the Since 1996, several authors have shown that in PD the contralateral to symptoms side the striatal uptake was uptake of 18F-DOPA in the basal ganglia is reduced, compa- decreased more than versus the other side [31-33]. Hilker et red to controls [27] and that in PD patients the rate of loss of al. (2005) [32] , using serial 18F-DOPA PET in 31 PD patients, dopaminergic neurons was faster compared with controls showed that 18F-DOPA was extensively metabolized in the [28]. The mean annual rate of decreased 18F-DOPA up-take in striatum and its metabolic products were retained in the PD patients was reported to be 8%-12% in the putamen and striatum during imaging. This nding described in terms of a 4%-6% in the caudate while in healthy volunteers was less single in ux constant, could be considered as irreversible, than 1% in both structures [27,29,30] . and could explain the distribution of the tracer. The ratio of 18 The uptake of F-DOPA PET in PD was more decreased in the net radioactivity of the stratium, corrected for the the posterior than in the anterior putamen and the caudate intravas-cular 18F-DOPA concentration from time 0 to the indicating that during the natural history of the disease end of acquisition, plotted against the ratio of integrated (Figure 2) putamen nuclei showed earlier involvement in plasma time activity and corrected for its metabolic activity respect to caudate nuclei while in healthy controls a mini- [25] showed a linear correlation and reached a pseudo- mal uptake di erence was shown between putamen and equilibrium, assuming of course that there was no tracer caudate (Figure 3). back ux. Others reported that in PD patients the 18F-DOPA PET image can be an index of the structural integrity of the nigro-striatal dopaminergic system because the decline rate of putaminal 18F-DOPA inversely correlated with disease duration indicating a negatively exponential loss of dopa- mine nigrostriatal neurons [34]. Since 18F-DOPA uptake depends on the number of functioning striatal cells, it is strictly proportional to these cell densities. Other authors [32] studied in PD patients the decline rate of the uptake of 18F-DOPA in putamen which was also found to be inversely related with disease duration suggesting a negative exponential loss of dopamine neurons in putamen. The annual disease progression rates ranged from 4.4% in the caudate to 6.3% in the putamen [32]. An average of 12% annual decline of 18F-DOPA uptake in baseline putamen was reported for a group of 17 PD patients [35]. Therefore, the required sample size to show the neuro-protection by the use of 18F-DOPA PET was increased according to the duration Figure 2. In a 57 years old patient with PD and predominant left side tremor, axial of symptoms of the patients. The above studies suggested 18F-DOPA PET view of the brain showed di use reduction of the uptake in both that the neurodegenerative process in PD followed a putamen and the right caudate. negative exponential course and slowed down with increased dura-tion of symptoms, contradicting the long- latency hypothesis of PD [36]. Other related papers also supported the above [33,34]. Symptoms onset and evolution of PD were also linked to disease progress, by the fact that the uptake of the tracer in the striatal body tended to decrease [27.30]. Nurmi E et al. (2001) [27] in 21 PD patients and in 8 volunteers showed that the disease process rst a ects the posterior and then the anterior putamen and the caudate nucleus. After the onset of PD, the absolute rate of decline of uptake of 18F-DOPA was the same in all patients. The preclinical period estimated from the decreased uptake in the posterior putamen was longer than if calculated from the anterior putamen and the caudate [30]. By 18F-DOPA PET analysis, other researchers [28] showed that the preclinical period was unlikely to last more than 7 years. On the other hand, Pal et al. (2002) [37] presented a 14 years old patient with juvenile PD, showing a severe reduction of caudate and putamen uptake, and a rostro-caudal gradient, Figure 3. Axial 18F-DOPA PET view of the brain showed homogeneous uptake of due to rapid loss of striatal neurons. This report seemed to the tracer in the basal ganglia of a healthy 58 years old volunteer, with di erence in suggest that juvenile parkinsonism is an aggressive type of PD the uptake between caudate and putamen. with a very short preclinical period while is commonly accepted
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that symptoms of PD do not appear until nigral cellsare lost Di erential diagnosis between PD and Parkinsonian in about 50% . Syndromes Recently, Picco et al. (2015) [39], in 15 patients with de One of the most important goals in early diagnosis and in novo PD drug-naive and 10 patients with ET as controls, identi cation of PD patients is the di erential diagnosis with 18 showed sig-ni cantly lower uptake of F-DOPA in striatum other PS, such as PSP, MSA and CBD, since only PD patients in PD patients than in controls, thus di erencing PD from ET well respond to anti-Parkinson drugs therapy. On the other patients. The main ndings provided by this work were the hand, in all other ND, the number of intact dopaminergic positive correlations of statistical parametric mapping neurons is considerably decreased and on this ground 18F- (SPM) analysis, to match the Tailarach coordinates , that DOPA PET could not be useful in the di erential diagnosis were found only in PD patients. These correlations between between all these diseases and PD. In one of the rst studies 18 the executive factor studied and F-DOPA uptake were on this topic, Otsuka et al. (1991) [43] investigated the 18F- found: a) in the bilateral anterior cingulate cortex and the DOPA uptake in 10 patients with MSA and 8 patients with middle frontal gyrus, b) between the verbal uency factor PD. The uptake of 18F-DOPA was reduced by a similar amount and the uptake in bilateral striata and c) between the visuo- in the putamen of both groups while there was a greater spatial factor and the uptake in bilateral anterior cingulate reduction of uptake in the caudate in MSA patients. These cortexes and bilateral striata. No correlations were found ndings were similar to another study conducted on 28 PD 18 between the F-DOPA uptake and either the verbal memory and 10 PSP patients. The uptake of the tracer was reduced in factor or the abstraction-working memory factor [39]. The both PSP and PD patients but there was a greater reduction above data explained in early PD the role of the mesocortical of uptake in the caudate of PSP patients in comparison with dopaminergic pathways in cognition and emphasized the PD patients. However, the overlapping between the two role of the medial frontal lobe and the anterior cingulate as populations was too much for a meaningful di erentiation the main sites of cortical correlation having executive and [44]. Similar results were reported for CBD by several other language functions. More recently, Marinelli et al. (2015), studies which showed a similar reduction of uptake in the con rmed the involvement of the orbito-frontal cortex in caudate and putamen of patients with CBD [45-47]. In a the develop-ment of cognitive abnormalities related to PD more recent study, Darcourt et al. (2014) showed that some [40]. Since the neurodegenerative loss of striatal neurons in patterns such as the asymmetrical faint homogeneous PD also concerns the frontal cortex through the mesocor- striatal uptake reduction pattern of CBD can correctly tical pathway, the above authors evaluated 16 drug naïve, identify patients with this disease [10]. Beyond the few newly diagnosed PD patients and 10 patients with ET, all availability of papers on this eld, an important suggestion right handed. They performed multiple-choice reaction was provided by Scher er et al (2013) who compared 18 time task, with the upper limb and underwent a F-DOPA healthy controls with PD patients, examining the uptake of PET brain scan. The reaction time was shorter in PD patients the tracer in the striatum and in the olfactory tract. and also tracer uptake was less in both striata, especially in Regarding the clinical implications of Braak's hypothesis the more a ec-ted hemisphere. [36] , which considers that the earliest signs of PD, such as Moreover, an inverse correlation was documented betwe- hyposmia, sleep disorders and constipation may precede en the average reaction time and the PET-assessed dopa- the motor features of the disease by several years, some minergic activity in the left, middle and inferior frontal gyri. researchers are increasingly focus on the "non-motor" Since all examined patients were right handed, this paper symptoms in order to detect early PD and to slow or stop its underlined the role of dopamine pathway in the lateral progression. In particular, Scher er et al (2013) found a orbitofrontal cortex in early staging of PD, and suggested in meaningful association in PD patients between the the goal-directed behavior that the compensatory cortical reduction of uptake in the striatum and in the olfactory tract dopamine region was related to movements preparation [40]. suggesting another criterion to distinguish between PD and The last two approaches in the diagnosis of PD by using other movement disorders [48]. 18F-DOPA uptake were strictly correlated with disease progress and with monitoring response to therapy [29]. Levodopa therapy may be neurotoxic for the remaining Comparison with SPET and other imaging dopaminergic neurons. In a study on 186 patients randomi- zed to ropirinole or levodopa therapy, 18F-DOPA PET scans modalities were performed as baseline and after 2 years of pharma- cological treatment [41]. It was concluded that the adminis- tration of ropinirole compared with levodopa was associa- The SPET scan with cocaine analogues is widely used in follow- ted with a relative by 30% slowing of the progression of PD up of the management of PD, for its easy production of as evidenced by serial 18F-DOPA uptake measurements. availability. It is also the main reference standard for evaluation of 18 Similar data were recorded after monitoring 21 patients the diagnostic performance of F-DOPA PET in the manage- who received implants of human fetal mesencephalic cells. ment of movement disorders. Several studies have shown the Sixteen of these patients by using a 18F-DOPA PET scan usefulness of SPET scan with dopamine receptors in the diag- nosis of PD and on the comparison between the diagnostic showed evidence of graft function over 6 months to 6 years 18 of follow-up [42]. performance of SPET and PET with F-DOPA in the management
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of patients with movement disorders [6, 42-52]. subgroups of PD patients in the ventral striatum, revealing a Eshuis et al. (2009) [53] studied the potential mismatches signi cantly lower cerebral rate of glucose metabolism betwe-en SPET with 123I-io upane and 18F-DOPA PET in within the ventral striatum for those patients with a symp- themanagement of patients with PD in comparison to a tomatology mostly akinetic-rigid in comparison with those group of healthy volunteers: Eleven patients with early stage with tremor-dominant symptomatology. PD and 17 patients with advanced PD were recruited. Results Others[61] investigated 30 patients with PD and 17 with were compared with those of 10 healthy volunteers submit- MSA, with susceptibility-weighted imaging (SWI) and 18F- ted to SPET and other 10 volunteers submitted to PET study. FDG PET and measured the signal intensity by SWI and the Both techniques were able to discriminate PD patients from standar-dized uptake value (SUV) of putamen nuclei. Both healthy controls. In particular, sensitivity and speci city in signal intensities and SUV signi cantly distinguished PD the early stage of the disease were 100% for both SPET and and MSA. On the 18F-FDG PET study low signal intensity in PET. When considering patients with advanced PD, the putamen correlated with hypometabolism. Comparison sensitivity was 91% for both tools while speci city was 100% with 18F-DOPA PET was not studied. In general, the role of 18F- for SPET and 90% for PET. Following the conclusion of the FDG PET in this eld is limited. above authors, both techniques could be feasible in the Other radiopharmaceuticals being beta-emitters have be- management of PD patients, especially in distinguishing en recently used to investigate patients with movement patients with early undiagnosed PD. This important nding disorders. The attention of researchers has also been focus-ed had been previously reported; by Ishikawa et al. (1996) [54] on labeling the receptors of the serotoninergic e ect and who evaluated 12 mildly a ected PD patients studied with evaluating the serotoninergic terminal function, by 11C- 123I-Io upane SPET and 18F-DOPA PET. Fifteen normal labeled 3-amino-4-(2-dimethylaminomethylphenylsul- volunteers served as controls for both tracers. Both tracers fanyl)-benzonitrile (11C-DASB) or by the dopamine releasing discriminated PD patients from controls with comparable (11C-raclopride) in levodopa-induced dyskinesias, a frequent accuracy. adverse motor e ect of therapy with levodopa in PD patients In a previous study on 13 patients with de novo PD and 17 [63]. Another study [64] indicated that striatal serotoninergic patients with advanced PD [55], performed by SPET with 123I- terminals contributed to the genesis of levodopa-induced io upane and PET with 18F-DOPA, using a template with dyskinesia, via aberrant processing of exogenous levodopa regions of interest to sample values of the caudate, and via the release of dopamine as false neurotransmitter in putamen and of an occipital reference region. A good the denervated striatum of PD patients with this adverse correlation between striatal 18F-DOPA uptake and striatal 123I- motor e ect. Beyond this paper, to the best of our know- io upane uptake and also between putaminal 18F-DOPA ledge, no other data have been reported in comparison with uptake and putaminal 123I-io upane uptake (was found, for 18F-DOPA PET or in early diagnosis of PD. both correla-tions P<0.0001). Striatal uptake of 123I-io upane Another radiopharmaceutical in the diagnosis of PD 18F- and of 18F-DOPA, moderately correlated with the stage of the uoro-m-tyrosine (18F-FMT) has been recently studied in disease and with motor scores but were equally able to comparison with 18F-DOPA [65, 66]. Standing to the fact that distinguish patients with advanced PD from patients with 18F-FMET is not a substrate for COMT, this tracer should have de novo PD [54]. These authors emphasized that, after the a better uptake-to-background ratio than 18F-DOPA. Others necessary premedication with carbidopa per os, they [65] investigated the possible role of 18F-FMT in diagnosing noticed a better reproducibility of 18F-DOPA PET. This could PD. Twelve patients at the early stage of PD were submitted be due to the shorter half-life of the tracer, the shorter time to both 18F-DOPA and 18F-FMT PET brain scans. By using volu- of the investigation and better resolution power of the 18F- mes of interest analysis, the researchers generated areas en- DOPA PET examination. compassing caudate, putamen and subregion of the puta- As a glucose analogue, the 18F-FDG is widely used as a PET men for both radiopharmaceuticals. The uptake of 18F-FMT tracer in oncology [56], cardiology [57]and neurology [58]. better depicted the clinical status of PD than did 18F-DOPA Fluorine-18-FDG PET and PET/CT is well known to be used uptake. The authors attributed this e ect to the higher a - in the management of cases disease with cognitive deterio- nity of 18F-FMT to the target, the AAAD. ration, but it cannot easily detect the reduction of metabol- The same group [66] deepened this preliminary experience ism in the striatum, due to its high rate of normal distribu- by examining further 15 patients with PD by means of both tion in normal brain structures opposite to 18F-DOPA. Thus, 18F-FET and 18F-DOPA PET as well as with high resolution MRI. 18F-FDG can only support the diagnosis of PS, by characte- Using a Patlak graphical approach, (explain acronym RDI) RDI rizing same speci c 18F-FDG uptake patterns when the clini- speci c uptake rate constants were generated. The uptake of cal diagnosis of PSP, MSA and CBD is uncertain [59]. 18F-FET was higher in extra striatal regions such as amygdala, Therefore, the attention of the researchers was focused on: pallidum, brainstem, hippocampus and thalamus, while the the potential usefulness of 18F-FDG PET in the di erential cortical uptake was similar for both tracers. They concluded diagnosis of PS[60], in diagnosing dementia complex asso- that the 18F-FET PET study may provide more advantages in ciated with PD [61]or in depicting di eren subgroups of PD depicting pathologic changes within allo-cortical loop patients, rather than diagnosing PD in the early stages. structures, which may contribute to deepen the knowledge Eggers et al. (2014)[62]: investigated 64 PD patients, 32 of about cognitive and emotional symptoms of PD [66] . which had a symptomatology prevalently akinetic-rigid and Concerning the MRI, the actual eld of interest of MRI in the 32 prevalently tremor-dominant, with 18F-DOPA and 18F- management of patients with movement disorders is FDG PET. They showed a clear di erence between the two actually limited to ensuring possible anatomical alterations
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that may occur in some parkinsonian syndromes and distin- in the basal ganglia inversely correlates with the severity of guish between PD patients from other ND. Similarly, MRI motor signs and with the duration of PD, 18F-DOPA theo- may help diagnose other diseases with a prevalent clinical retically should be associated to a lower dosimetry for the subset of tremor, such as vascular parkinsonism or Fahr's patients, although this point needs to be further studied. syndrome[67,68] or other disorders where typical anatomi- Finally, because the decline of DAT binding examined by cal alterations re ect the anatomo-pathological substrate of SPET is also related to age and not only to disease duration, the disease, like PSP, MSA and CBD [44, 69]. In PD, the casual the uptake of 18F-DOPA can be a better marker in the diag- depletion of transmitters cannot be detected by this imag- nosis and monitoring of PD patients. ing modality with the accuracy of molecular imaging provi- Considering the heterogeneity of 18F-DOPA PET acqui- ded by SPET and PET radiopharmaceuticals. Nevertheless, sition protocols, it is necessary to consider that all main researchers recently focused on the possible role of an advantages could be e ectively achieved only by standar- integrated evaluation of PD by means of both MRI and PET dizing acquisition protocols, using premedication with [70]. The main suggestion in this eld was the potential carbidopa and acquiring the image of the whole brain at 90 usefulness of MRI to exclude symptomatic parkinsonism due minutes after the tracer administration. Furthermore, it is to structural basal ganglia cells loss, not by image analysis, necessary to standardize a unique model of quantitation of since the loss of cells is re ected only in the advanced stage PET data[62]. Positron emission tomography radiopharma- of the disease, but by di usion-weighted and inversion reco- ceuticals other than 18F-DOPA used for imaging in movement very MRI [71]and by MR spectroscopy (MRS) [72] . disorders seem to actually play a limited role in this eld, with Recent studies supported the usefulness of an integrated the exception of 18F-FMT, showing interesting preliminary PET/MRI evaluation to ensure the diagnosis of PD by ndings [65, 66] which need to be further studied. perfusion and anatomy provided by glucose metabolism of Regarding the availability of 18F-DOPA PET technology, the 18F-FDG PET [73] or the metabolism of the striatum provided recent development of automated synthesis module [77] for by 18F-DOPA PET [74] and MRI. A better resolution a higher the production of this tracer directly in the provided PET partial volume e ect correction and an advanced head centers, helps the availability of 18F-DOPA for researchers and movement correction are applied in this eld [75] . clinicians. Magnetic Resonance imaging is the method of choice in the management of several ND is providing high quality Discussion images with excellent anatomical information and is increasingly the preferred technique for studying both functional and structural data. Position emission tomo- graphy is still the best technique to study the in vivo It has been shown the potential usefulness of PET with 18F- behavior of neurotransmitters and neuroreceptors. The DOPA in diagnosing PD. As an extremely useful diagnostic rapid development of hybrid PET/MRI could help to tool for the non-invasive evaluation of basal ganglia patho- potentiate and improve the diagnostic performance of both physiology in both patients with PD and PS, like PSP, CBD techniques. In particular, MRI improves the placement of and MSA, since the semi-quantitative analysis of the uptake regions of interest in PET images, for a better quantitation of in the caudatum could help their di erential diagnosis with the uptake of the tracer in substantia nigra and also o ers PD. The limit of some cited studies was the small number of new quantitation approaches like the support vector examined patients but results were very encouraging in machines (SVM), a recently developed operator-indepen- absolute terms of sensitivity and speci city, especially when dent MR technique of quantitation that can distinguishing compared with SPET. The knowledge of molecular alter- ET from PD patients [78], as already reported for SPET with 123 ations in PD provided by 18F-DOPA PET o ered to a better I-nortropane [79] . identi cation of the disease in the pre-clinical stage and a Since ET is a clinical condition involving the upper limbs, better monitoring of disease progress and/or response to usually known as a postural tremor with or without kinetic therapy. The pharmacological e ects of concomitant tremor, it could be a diagnostic dilemma in the di erential 18 symptomatic treatments and of neuro-protective agents on diagnosis with PD. The F-DOPA PET shows a normal uptake the tracer uptake still needs to be addressed and speci cally on the striatum in patients with ET compatible with the the study of drugs, such as levodopa-inducing dyskinesia intact nigro-striatal dopaminergic neurons while recent [63, 64, 76] . studies on MRI suggested a possible involvement of the It is necessary to consider some important features related cerebellum in the pathophysiology of this disease [80, 81]. to the traditional SPET imaging: beyond the substantial Future studies are needed to verify if the combination of similarity in terms of sensitivity and speci city between SPET functional and metabolic data provided by MRI and PET using 18 scan with cocaine analogues and PET with 18F-DOPA, some F-DOPA can reciprocally implement their diagnostic impact factors support of the last technique in the management of in a single-step, functional and anatomical whole brain PD patients with predominant resting tremor, because evaluation [82, 83], especially referring to ET and other PS. It is 18 having a better resolution limit in a shorter time acquisition noteworthy to mention that the F-DOPA PET is currently also protocol, it could minimize the artifacts due to the move- employed in other diseases involving the basal ganglia or the ments of the patients. Moreover, for the same reasons, alt- dopaminergic system, such as epilepsy [84], detoxi ed alco- hough the uptake of both cocaine analogues and 18F-DOPA holism patients [85] and psychiatric disorders [86]. Since atypi-
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cal Parkinsonism and other neurodegenerative diseases 16. Kumakura Y, Danielsen EH, Reilhac A et al. Levodopa e ect on 18 such as PSP, MSA and CBD do not respond to therapy with [ F] uorodopa in ux to brain: normal volunteers and patients levodopa, the development of the PET/MRI scanner and new with Parkinson's disease. Acta Neurol Scand 2004; 110: 188-95. 17. Taieb D, Timmers HJ, Hindie E et al. EANM 2012 guidelines for radiopharmaceuticals will considerably expand our radionuclide imaging of phaemocromocytoma and paragan- knowledge in this eld. glioma. E J Nucl Med Mol Imaging 2012; 39: 1977-95. 18. Sawle GV, Burn DJ, Morrish PK et al. The e ect of entacapone (OR- 611) on brain [18F]-6-L- uorodopa metabolism: implications for Acknowledgment levodopa therapy of Parkinson's disease. Neurology 1994; 44: The Authors wish to thank their collaborators Technicians 1292-7. Radiologists Domenico Gullà and Federico Rocca for the 19. del Amo EM, Urtti A, Yliperttula M. 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Salvator Dali, Mimicking the painting of Velasqueth, the Dwarf Sebastian de Moro and adding fried eggs himsef. Mixed technique in canvas.
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